Unraveling the Structure-Affinity Relationship between Cucurbit[n]urils (n = 7, 8) and Cationic Diamondoids

We report the measurement of the binding constants (K_a) for cucurbit[n]uril (n = 7, 8) toward four series of guests based on 2,6-disubstituted adamantanes, 4,9-disubstituted diamantanes, 1,6-disubstituted diamantanes, and 1-substituted adamantane ammonium ions by direct and competitive ¹H NMR spectroscopy. Compared to the affinity of CB[7]·Diam(NMe₃)₂, the adamantane diammonium ion complexes (e.g., CB[7]·2,6-Ad(NH₃)₂ and CB[7]·2,6-Ad(NMe₃)₂) are less effective at realizing the potential 1000-fold enhancement in affinity due to ion-dipole interactions at the second ureidyl C═O portal. Comparative crystallographic investigation of CB[7]·Diam(NMe₃)₂, CB[7]·DiamNMe₃, and CB[7]·1-AdNMe₃ revealed that the preferred geometry positions the ⁺NMe₃ groups ≈0.32 Å above the C═O portal; the observed 0.80 Å spacing observed for CB[7]·Diam(NMe₃)₂ reflects the simultaneous geometrical constraints of CH₂···O═C close contacts at both portals. Remarkably, the CB[8]·IsoDiam(NHMe₂)₂ complex displays femtomolar binding affinity, placing it firmly alongside the CB[7]·Diam(NMe₃)₂ complex. Primary or quaternary ammonium ion looping strategies lead to larger increases in binding affinity for CB[8] than for CB[7], which we attribute to the larger size of the carbonyl portals of CB[8]; this suggests routes to develop CB[8] as the tightest binding host in the CB[n] family. We report that alkyl group fluorination (e.g., CB[7]·1-AdNH₂Et versus CB[7]·1-AdNH₂CH₂CF₃) does not result in the expected increase in K_a value. Finally, we discuss the role of solvation in nonempirical quantum mechanical computational methodology, which is used to estimate the relative changes in Gibbs binding free energies.